Bipolar Disorder, Depression
Conditions
Keywords
Major Depressive Disorder, MDD, Bipolar Disorder, BD, Depression, Major Depressive Disorder with Bipolar features
Brief summary
The primary outcome of this study is to determine if predictors of response can select a population of patients with MDD that is effectively treatable by augmentation with ziprasidone. Major depressive disorder (MDD) is a broad category, including many forms of depressive illness, including those with only a single major depressive episode, those with episodic recurrence with intervening well states, those with chronic depressive/anxious states without intervening euthymia, and those with manic symptoms that do not meet threshold definitions of full mania/hypomania. In this heterogenous, large diagnostic definition, important groups of patients do not appear to respond well to antidepressants, and, conversely, based on observational studies, may respond well to neuroleptics. These predictors of response have begun to be identified and may serve to better design studies of neuroleptics in depressive illnesses. Among these predictors of response in MDD are clinical features that are more similar to bipolar illness than unipolar depression. These include a family history of bipolar disorder, antidepressant-induced mania, highly recurrent depressive episodes (\>5), atypical depression, early age of onset of depression (\< age 20), failure to respond to antidepressants, and antidepressant tolerance (initial response followed by later loss of response). The investigators propose to use these predictors to pick out patients that are more likely to respond to Geodon for MDD. This will be the first RCT of these predictors of depressive response applied to neuroleptics.
Detailed description
This will be a three-site, block randomized (1:1 ratio) double-blind, placebo-controlled prospective cross-over study with 50 subjects. Patients will be randomized to receiving ziprasidone-washout-placebo or placebo- washout-ziprasidone for 13-weeks. Primary and Secondary and safety outcomes: The primary outcome measure will be change from baseline Montgomery-Asberg Depression Rating Scale (MADRS) score to end of treatment. Safety outcomes will be determined by spontaneously reported adverse events on the case report form.
Interventions
DRUGziprasidone
Ziprasidone will be administered as a pill. The once-daily total daily dose will be 80-160 mg/d of ziprasidone. Dosing will begin at 20 mg BID with an escalation strategy based on target symptoms and tolerability, with a target dose range of 80-160 mg/d. Dose escalations will occur by increments of 20-40 mg weekly.
DRUGSugar pill
The once-daily total daily dose will be 80-160 mg/d of the sugar pill. Dosing will begin at 20 mg BID with an escalation strategy based on target symptoms and tolerability, with a target dose range of 80-160 mg/d. Dose escalations will occur by increments of 20-40 mg weekly.
Sponsors
Duke University
University of South Carolina
Tufts Medical Center
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
1. Age 18-70 years. 2. If female, nonpregnant/nonlactating 3. If a sexually active female of reproductive potential, must be using adequate contraception (i.e., oral contraceptives, barrier protection, or prior tubal ligation) 4. Currently meets DSM-IV criteria for a major depressive episode, non-psychotic. 5. Having at least 3 of the following criteria listed for predictors of depressive response to neuroleptics: a family history of bipolar disorder, antidepressant-induced mania, highly recurrent depressive episodes (\>5), atypical depression, early age of onset of depression (\< age 20), failure to respond to antidepressants, and antidepressant tolerance (initial response followed by later loss of response). Inadequate response to antidepressants is identified as follows: having a score of ≥14 on the 17-item HAMD or a CGI-S score of ≥ 3 after a retrospective confirmation of an adequate trial of a single antidepressant (defined as a ≥ 6-week trial of acceptable therapeutic dose \[≥ 40 mg of fluoxetine, paroxetine or citalopram, 20 mg of escitalopram, 60 mg of duloxetine, 37.5 mg of paroxetine CR, 150 mg of sertraline, 100 mg of fluvoxamine, 225 mg of venlafaxine XR, 30 mg of mirtazapine, 300 mg of bupropion, 75 mg of nortriptyline, 20 mg of protriptyline, 100 mg of amitriptyline or imipramine)
Exclusion criteria
1. Bipolar depression 2. Sensitivity to or failure to respond to ziprasidone by history or ziprasidone use in previous 3 months 3. Active substance abuse or dependence in the previous 3 month 4. Psychotic disorders 5. Serious suicidality as evidenced by score of 3 or greater on suicide item of MADRS 6. Medically unstable as judged by study investigators 7. Lack of capacity to provide informed, written, consent to investigators 8. Previous diagnosed cardiac arrhythmias
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| MADRS Improvement Over 6 Weeks | 13 weeks (Two 6 week periods plus a one week washout) | Montgomery Asberg Depression scale improvement was assessed in two 6 week crossover periods. Minimum score on MADRS is 0, the maximum is 60. Higher scores represent a worse outcome, i.e., greater severity of depressive symptoms. Scores of about 20 and above are generally seen as consistent with being in a full major depressive episode. No subscales were used or combined. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Predictors of Bipolarity to Define the Study Population | 13 weeks | The specific bipolarity predictors in patients with MDD were assessed. |
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| All Study Participants All participants were randomized to either placebo followed by ziprasidone crossover, or ziprsidone followed by placebo crossover. | 49 |
| Total | 49 |
Baseline characteristics
| Characteristic | All Study Participants |
|---|---|
| Age, Continuous | 42.6 years STANDARD_DEVIATION 11.4 |
| Sex: Female, Male Female | 33 Participants |
| Sex: Female, Male Male | 16 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 0 / 49 | 21 / 49 |
| serious Total, serious adverse events | 0 / 49 | 1 / 49 |
Outcome results
Primary
MADRS Improvement Over 6 Weeks
Montgomery Asberg Depression scale improvement was assessed in two 6 week crossover periods. Minimum score on MADRS is 0, the maximum is 60. Higher scores represent a worse outcome, i.e., greater severity of depressive symptoms. Scores of about 20 and above are generally seen as consistent with being in a full major depressive episode. No subscales were used or combined.
Time frame: 13 weeks (Two 6 week periods plus a one week washout)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | MADRS Improvement Over 6 Weeks | 10.0 units on a scale | Standard Deviation 10.3 |
| Ziprasidone | MADRS Improvement Over 6 Weeks | 6.7 units on a scale | Standard Deviation 8.2 |
Comparison: Linear mixed effects regression modelp-value: 0.48Mixed Models Analysis
Secondary
Predictors of Bipolarity to Define the Study Population
The specific bipolarity predictors in patients with MDD were assessed.
Time frame: 13 weeks
Population: The most common predictor was antidepressant tolerance, as reported below in 37 subjects.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo | Predictors of Bipolarity to Define the Study Population | Antidepressant tolerance | 75.0 percentage of subjects |
| Placebo | Predictors of Bipolarity to Define the Study Population | Antidepressant nonresponse | 73.5 percentage of subjects |
| Placebo | Predictors of Bipolarity to Define the Study Population | Highly recurrent depressive episodes | 72.3 percentage of subjects |
| Placebo | Predictors of Bipolarity to Define the Study Population | Atypical depression | 52.9 percentage of subjects |
| Placebo | Predictors of Bipolarity to Define the Study Population | Family history of bipolar disorder | 46.0 percentage of subjects |
| Placebo | Predictors of Bipolarity to Define the Study Population | Early age of onset | 47.6 percentage of subjects |
| Placebo | Predictors of Bipolarity to Define the Study Population | Antidepressant-induced mania | 8.8 percentage of subjects |